Virtually all approved medications for schizophrenia are mixed dopamine (DA) D2-family (D2, 3 and 4) receptor antagonists or partial agonists with limited - if any - preference for specific subtypes of D2-family receptors. Selective D3 antagonists may represent a novel class of antipsychotics that lack the major side effects of non- selective antagonists. One valuable, translational and predictive model for antipsychotic action is prepulse inhibition (PPI), an operational measure of sensorimotor gating, that is impaired in unmedicated schizophrenia patients. The long term goals of this application are to identify molecular targets for drug discovery and link in vivo and ex vivo assays of pharmacological treatments by characterizing the intracellular signaling pathways of D3 receptor activation that regulate sensorimotor gating. The first aim is to determine the behavioral effects of D3 receptor activation in the rat. Preferential D3 agonists such as pramipexole (PRA) PD128907, or 7-OH- DPAT will be administered alone or after either SB277,011, a D3-selective antagonist, or L741,626, a D2- selective antagonist. Agonist-induced changes in PPI and other behaviors will be measured, and the role of D2 vs. D3 receptors will be determined by their blockade with selective antagonists, and by comparison with the D2-selective agonist, sumanirole. Based on these data, the most D3-specific agonist and dose will be used for subsequent studies in Aim 2. The second aim is to determine the intracellular effects of D3 receptor activation in the rat. DA-linked signal transduction molecules in the nucleus accumbens (NAC) will be assayed for: GTP3S binding, adenylate cyclase activity, PKA activity, CREB phosporylation, c-fos expression, ERK1/2 activity, MSK1 activity, and Elk-1 levels. The order of assays will permit the most efficient assessment of the the targeted signal pathways. Signaling molecule levels will also be measured in the dorsal striatum for comparison. The third aim is to test the role of signaling molecules identified in Aim 2 in D3-mediated behavioral effects identified in Aim 1 by altering signaling cascade activity via intracerebral infusion of inhibitors or activators of the relevant pathways. An example appropriate for the cAMP/PKA pathway would involve intra- NAC infusion of Rp-cAMPS (a competitive inhibitor of cAMP binding) prior to PPI testing. An intervention "downstream" of either the cAMP/PKA or MAPK/ERK pathways would be involve intra-NAC infusion of CREB antisense oligonucleotide. Clarifying the divergence in signaling pathways that control D2- and D3-regulation of PPI has translational potential for guiding the development of novel inference-based antipsychotics. Furthermore, signaling molecules that mediate PPI deficits might be linked to the pathophysiology of schizophrenia and related disorders, and thus the proposed study would provide a physiological context for genes identified in neuropsychiatric genetic linkage studies. PUBLIC HEALTH RELEVANCE: Project Narrative Schizophrenia is a chronic, severe, debilitating brain disorder that affects about 1% of the population in the U.S. and worldwide, with symptoms usually beginning in early adulthood. We still have much to learn about this disorder, but promising new research linking changes in brain chemistry with severe symptoms may lead to improvements in care for schizophrenia patients, through the development of new medications with greater efficacy and fewer side effects. Through our studies, we hope to expand our understanding of biological systems related to schizophrenia and to apply these advancements directly towards improving the treatment options for patients.